Fragile X syndrome carriers have FMR1 alleles, called premutations, with an intermediate number of 5'- untranslated CGG-repeats between patients (>200 repeats) and normal individuals (<60 repeats). Some fragile X premutation carriers manifest a neurodegenerative disease with ataxia and tremor, Fragile-X- Associated Tremor/Ataxia Syndrome (FXTAS). The long-term goal of this project is to understand the molecular pathogenesis of FXTAS. Since FMR1 premutation alleles uniquely produce more FMR1 transcripts with an elongated CGG repeat, it has been speculated that premutation rCGG repeats cause the neurodegenerative disease in carriers. A Drosophila model of FXTAS has been created by generating flies that express either normal or expanded untranslated-CGG repeats. This fly model recapitulates the cellular phenotypes observed in FXTAS patients including progressive neuronal degeneration and the formation of inclusions, and demonstrates that fragile X premutation rCGG repeats are toxic and lead to RNA-mediated neurodegeneration. This proposal focuses on delineating the molecular mechanism by which fragile X premutation rCGG repeats cause neurodegeneration using the developed fly model. Three Specific Aims are proposed: 1) To determine the specificity of fragile X premutation rCGG repeats-mediated neuronal cell death/neurodegeneration; 2) To identify the Drosoohila rCGG-repeat-Binding Proteins (rCGGBPs) and test the hypothesis that rCGGBPs play roles in rCGG-mediated neurodegeneration; 3) To identify the novel suppressors and enhancers of rCGG-mediated neurodegeneration through a large-scale genetic screen. Successful completion of these studies should significantly advance our understanding of the molecular pathogenesis of FXTAS. Identification of genes and pathways involved in FXTAS will provide valuable targets for future pharmacological research aimed at developing drugs for therapy. [unreadable] [unreadable]